A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension

Background

Despite advances in drug therapy that target the endothelin, nitric oxide and prostacyclin pathways, pulmonary arterial hypertension (PAH) has still a poor prognosis [1-3]. Measures at baseline and during follow-up that reflect right ventricular performance, predict outcome [3-5]. Treatment protocols advocate a goal-oriented approach, meaning to achieve a low-risk profile preferably based on functional class (FC), exercise capacity and right ventricular function, which is included in a risk assessment instrument presented in the ESC/ERS guidelines as of 2009 [6,7].

It is possible that variables that are included in this risk assessment instrument predict prognosis during follow-up, however this is incompletely validated (level of evidence C) [4,5]. The goal of this study was to test the discriminatory ability of the risk assessment instrument, using the Swedish PAH register (SPAHR, started in 2008 [8]), and to explore the potential prognostic advantage of a low-risk profile at follow-up which was performed within one year from baseline. For this, 7 variables per patient were assessed at baseline and 5 during follow-up. The study included 261 patients with idiopathic PAH (IPAH), 7 with familiar PAH (FPAH), 162 with connective tissue disease-associated PAH (APAH-CTD), 67 with coronary heart disease-associated PAH (APAH-CHD), 16 with drugs- and toxins-induced PAH, 3 with HIV-associated PAH and 14 with portal hypertension-associated PAH. Median time to first follow-up was 4 months and total follow-up 27 months.

Main results

At baseline, low-risk, intermediate-risk and high-risk corresponded to 23%, 67% and 10% of patients respectively. Age was on average lower in the low-risk group compared to intermediate (P<0.001) and high-risk (P=0.004) groups.

At follow-up, intermediate-risk and high-risk corresponded to 29%, 60% and 11% of patients respectively. Also now, age was on average lower in the low-risk group compared to intermediate (P<0.001) and high-risk groups (P<0.001).

Survival after 1, 3 and 5 years based on baseline risk groups were 99, 95 and 85% respectively for the low-risk group, 83, 67 and 52% respectively for the intermediate-risk group and 74, 51 and 35% for the high-risk group (P<0.001 for difference between risk groups).

Survival after 1, 3 and 5 years based on follow-up risk groups were 99, 97 and 92% respectively for the low-risk group, 91, 73 and 56% respectively for the intermediate-risk group and 27, 25 and 6% for the high-risk group (P<0.001 for difference between risk groups).

Survival for patients that remained in the low-risk group after 1, 3 and 5 years was 100, 98 and 89% respectively. This was 98, 96 and 96% for those who improved to low-risk. Accordingly, for those who remained in the intermediate-risk of high-risk groups survival was 90, 68 and 50% after 1, 3 and 5 years respectively and 81, 60 and 43% for those who worsened to intermediate or high-risk.

After multivariable correction (age, sex and PAH subsets), mortality risk was reduced for patients in the low-risk group at follow-up (HR 0.2, 95% CI 0.1-0.4, P<0.001).

Survival was also better for patients with a higher proportion of variables that were categorized as low-risk.

Conclusion

These results support the use of comprehensive risk assessments and goal-oriented treatment approach towards a low-risk profile, as proposed by the ESC/ERS guidelines 2015. Moreover, the fact that only 29% of patients were in the low-risk group at follow-up, urges for better treatments and treatment strategies in general. Furthermore, the risk assessment successfully discriminates patients with better or worse outcome both at baseline and at follow-up, in which determination at follow-up better predicts long-term outcome.

19. Galiè N, Humbert M, Vachiéry JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67–119.